The treatment of pain, in particular of neuropathic pain, is very important in medicine. There is a worldwide demand for effective pain therapies. The urgent need for action for a patient-focused and target-oriented treatment of chronic and non-chronic states of pain, this being understood to mean the successful and satisfactory treatment of pain for the patient, is also documented in the large number of scientific studies which have recently appeared in the field of applied analgesics or basic research on nociception.
The subtype 1 vanilloid receptor (VR1/TRPV1), which is often also referred to as the capsaicin receptor, is a suitable starting point for the treatment of pain, in particular of pain selected from the group consisting of acute pain, chronic pain, neuropathic pain and visceral pain. This receptor is stimulated inter alia by vanilloids such as capsaicin, heat and protons and plays a central role in the formation of pain. In addition, it is important for a large number of further physiological and patho-physiological processes and is a suitable target for the therapy of a large number of further disorders such as, for example, migraine, depression, neurodegenerative diseases, cognitive disorders, states of anxiety, epilepsy, coughs, diarrhoea, pruritus, inflammations, disorders of the cardiovascular system, eating disorders, medication dependency, misuse of medication and urinary incontinence.
There is a demand for further compounds having comparable or better properties, not only with regard to affinity to vanilloid receptors 1 (VR1/TRPV1 receptors) per se (potency, efficacy).
Thus, it may be advantageous to improve the metabolic stability, the solubility in aqueous media or the permeability of the compounds. These factors can have a beneficial effect on oral bioavailability or can alter the PK/PD (pharmacokinetic/pharmacodynamic) profile; this can lead to a more beneficial period of effectiveness, for example. A weak or non-existent interaction with transporter molecules, which are involved in the ingestion and the excretion of pharmaceutical compositions, is also to be regarded as an indication of improved bioavailability and at most low interactions of pharmaceutical compositions. Furthermore, the interactions with the enzymes involved in the decomposition and the excretion of pharmaceutical compositions should also be as low as possible, as such test results also suggest that at most low interactions or no interactions at all, of pharmaceutical compositions are to be expected.
It was therefore an object of the invention to provide novel compounds, preferably having advantages over the prior-art compounds. The compounds should be suitable in particular as pharmacological active ingredients in pharmaceutical compositions, preferably in pharmaceutical compositions for the treatment and/or prophylaxis of disorders or diseases which are at least partially mediated by vanilloid receptors 1 (VR1/TRPV1 receptors).
This object is achieved by the subject matter described herein.
It has surprisingly been found that the substituted compounds of general formula (I), as given below, display outstanding affinity to the subtype 1 vanilloid receptor (VR1/TRPV1 receptor) and are therefore particularly suitable for the prophylaxis and/or treatment of disorders or diseases which are at least partially mediated by vanilloid receptors 1 (VR1/TRPV1).
Particularly suitable are substituted compounds of general formula (I), as given below, that in addition to their activity with regard to the VR1-receptor show one or more additional advantageous properties, for example, suitable potency, suitable efficacy, no increase in body temperature and/or heat pain threshold; appropriate solubility in biologically relevant media such as aqueous media, in particular in aqueous media at a physiologically acceptable pH value, such as in buffer systems, for instance in phosphate buffer systems; suitable metabolic stability and diversity (e.g. sufficient stability towards the oxidative capabilities of hepatic enzymes such as cytochrome P450 (CYP) enzymes and sufficient diversity with regard to the metabolic elimination via these enzymes); and the like.
In a first aspect of the present invention, the present invention relates to a substituted compound of general formula (I),
    wherein    X represents O or S;    Y represents O, S or N—CN;    Z represents N(R3b) or C(R4aR4b);    R1 represents aryl or heteroaryl,            wherein said aryl or heteroaryl may be unsubstituted or mono- or independently polysubstituted by one or more substituents, selected from the group consisting of H, F, Cl, Br, CN, OH, C1-4-alkyl, hydroxy-C1-4-alkyl, halo-C1-4-alkyl, cyano-C1-4-alkyl, C1-4-alkoxy-C1-4-alkyl, hydroxy-C1-4-alkoxy, halo-C1-4-alkoxy, cyano-C1-4-alkoxy, C1-4-alkoxy-C1-4-alkoxy, C1-4-alkylS(O), hydroxy-C1-4-alkylS(O), halo-C1-4-alkylS(O), cyano-C1-4-alkylS(O), C1-4-alkoxy-C1-4-alkylS(O), C1-4-alkylS(O)2, hydroxy-C1-4-alkylS(O)2, halo-C1-4-alkylS(O)2, cyano-C1-4-alkylS(O)2, C1-4-alkoxy-C1-4-alkylS(O)2, H2N, (C1-4-alkyl)(H)N, (hydroxy-C1-4-alkyl)(H)N, (halo-C1-4-alkyl)(H)N, (cyano-C1-4-alkyl)(H)N, (C1-4-alkoxy-C1-4-alkyl)(H)N, (C3-6-cycloalkyl)(H)N, (C3-7-heterocycloalkyl)(H)N, (C1-4-alkyl)2N, (hydroxy-C1-4-alkyl)(C1-4-alkyl)N, (halo-C1-4-alkyl)(C1-4-alkyl)N, (cyano-C1-4-alkyl)(C1-4-alkyl)N, (C1-4-alkoxy-C1-4-alkyl)(C1-4-alkyl)N, (C3-6-cycloalkyl)(C1-4-alkyl)N, (C3-7-heterocycloalkyl)(C1-4-alkyl)N, (hydroxy-C1-4-alkyl)2N, (C3-6-cycloalkyl)(hydroxy-C1-4-alkyl)N and (C3-7-heterocycloalkyl)(hydroxy-C1-4-alkyl)N,            R2 represents C1-4-alkyl, hydroxy-C1-4-alkyl, halo-C1-4-alkyl, cyano-C1-4-alkyl, C1-4-alkoxy-C1-4-alkyl, C3-6-cycloalkyl or (C3-6-cycloalkyl)-C1-4-alkyl;    R3a and R3b each independently represent H, C1-4-alkyl, hydroxy-C1-4-alkyl, halo-C1-4-alkyl, cyano-C1-4-alkyl or C1-4-alkoxy-C1-4-alkyl;    R4a and R4b each independently represent H, F, Cl, CN, C1-4-alkyl, hydroxy-C1-4-alkyl, halo-C1-4-alkyl, cyano-C1-4-alkyl or C1-4-alkoxy-C1-4-alkyl;    or    R4a and R4b together with the carbon atom connecting them form a C3-6-cycloalkyl or a C3-7-heterocycloalkyl;    Ar represents aryl or heteroaryl,            wherein said aryl or heteroaryl may be condensed with an aromatic or aliphatic ring to form a bicycle,        and wherein said aryl or heteroaryl and said condensed aromatic or aliphatic ring each independently may be unsubstituted or mono- or independently polysubstituted by one or more substituents, selected from the group consisting of F, Cl, Br, CN, OH, ═O, C1-4-alkyl, hydroxy-C1-4-alkyl, halo-C1-4-alkyl, cyano-C1-4-alkyl, C1-4-alkoxy-C1-4-alkyl, hydroxy-C1-4-alkoxy, halo-C1-4-alkoxy, cyano-C1-4-alkoxy, C1-4-alkoxy-C1-4-alkoxy, hydroxy-C1-4-alkoxy-C1-4-alkyl, C1-4-alkylS(O), hydroxy-C1-4-alkylS(O), halo-C1-4-alkylS(O), cyano-C1-4-alkylS(O), C1-4-alkoxy-C1-4-alkylS(O), C1-4-alkylS(O)2, hydroxy-C1-4-alkylS(O)2, halo-C1-4-alkylS(O)2, cyano-C1-4-alkylS(O)2, C1-4-alkoxy-C1-4-alkylS(O)2, C1-4-alkylS(O)C1-4-alkyl, hydroxy-C1-4-alkylS(O)C1-4-alkyl, C1-4-alkylS(O)2C1-4-alkyl, hydroxy-C1-4-alkylS(O)2C1-4-alkyl, H2N, (C1-4-alkyl)(H)N, (hydroxy-C1-4-alkyl)(H)N, (halo-C1-4-alkyl)(H)N, (cyano-C1-4-alkyl)(H)N, (C1-4-alkoxy-C1-4-alkyl)(H)N, (C3-6-cycloalkyl)(H)N, (C3-7-heterocycloalkyl)(H)N, (C1-4-alkyl)2N, (hydroxy-C1-4-alkyl)(C1-4-alkyl)N, (halo-C1-4-alkyl)(C1-4-alkyl)N, (cyano-C1-4-alkyl)(C1-4-alkyl)N, (C1-4-alkoxy-C1-4-alkyl)(C1-4-alkyl)N, (C3-6-cycloalkyl)(C1-4-alkyl)N, (C3-7-heterocycloalkyl)(C1-4-alkyl)N, (hydroxy-C1-4-alkyl)2N, (C3-6-cyclo-alkyl)(hydroxy-C1-4-alkyl)N, (C3-7-heterocycloalkyl)(hydroxy-C1-4-alkyl)N, (H)2NC1-4-alkyl, [(C1-4-alkyl)(H)N](C1-4-alkyl), [(hydroxy-C1-4-alkyl)(H)N](C1-4-alkyl), [(halo-C1-4-alkyl)(H)N](C1-4-alkyl), [(cyano-C1-4-alkyl)(H)](C1-4-alkyl), [(C1-4-alkoxy-C1-4-alkyl)(H)N](C1-4-alkyl), [(C3-6-cycloalkyl)(H)N](C1-4-alkyl), [(C3-7-heterocycloalkyl)(H)N](C1-4-alkyl), [(C1-4-alkyl)2N](C1-4-alkyl), [(hydroxy-C1-4-alkyl)(C1-4-alkyl)N](C1-4-alkyl), [(halo-C1-4-alkyl)(C1-4-alkyl)N](C1-4-alkyl), [(cyano-C1-4-alkyl)(C1-4-alkyl)N](C1-4-alkyl), [(C1-4-alkoxy-C1-4-alkyl)(C1-4-alkyl)N](C1-4-alkyl), [(C3-6-cycloalkyl)(C1-4-alkyl)N](C1-4-alkyl), [(C3-7-heterocycloalkyl)(C1-4-alkyl)N](C1-4-alkyl), [(hydroxy-C1-4-alkyl)2N](C1-4-alkyl), [(C3-6-cycloalkyl)(hydroxy-C1-4-alkyl)N](C1-4-alkyl), [(C3-7-heterocycloalkyl)(hydroxy-C1-4-alkyl)N](C1-4-alkyl), H2NC(O), (C1-4-alkyl)(H)NC(O), (hydroxy-C1-4-alkyl)(H)NC(O), (halo-C1-4-alkyl)(H)NC(O), (cyano-C1-4-alkyl)(H)NC(O), (C1-4-alkoxy-C1-4-alkyl)(H)NC(O), (C3-6-cyclo-alkyl)(H)NC(O), (C3-7-heterocycloalkyl)(H)NC(O), (C1-4-alkyl)2NC(O), (hydroxy-C1-4-alkyl)(C1-4-alkyl)NC(O), (halo-C1-4-alkyl)(C1-4-alkyl)NC(O), (cyano-C1-4-alkyl)(C1-4-alkyl)NC(O), (C1-4-alkoxy-C1-4-alkyl)(C1-4-alkyl)NC(O), (C3-6-cycloalkyl)(C1-4-alkyl)NC(O), (C3-7-heterocycloalkyl)(C1-4-alkyl)NC(O), (hydroxy-C1-4-alkyl)2NC(O), (C3-6-cycloalkyl)(hydroxy-C1-4-alkyl)NC(O), (C3-7-heterocycloalkyl)(hydroxy-C1-4-alkyl)NC(O), H2NS(O)2, (C1-4-alkyl)(H)NS(O)2, (hydroxy-C1-4-alkyl)(H)NS(O)2, (halo-C1-4-alkyl)(H)NS(O)2, (cyano-C1-4-alkyl)(H)NS(O)2, (C1-4-alkoxy-C1-4-alkyl)(H)—NS(O)2, (C3-6-cycloalkyl)(H)NS(O)2, (C3-7-heterocycloalkyl)(H)NS(O)2, (C1-4-alkyl)2NS(O)2, (hydroxy-C1-4-alkyl)(C1-4-alkyl)NS(O)2, (halo-C1-4-alkyl)(C1-4-alkyl)NS(O)2, (cyano-C1-4-alkyl)(C1-4-alkyl)NS(O)2, (C1-4-alkoxy-C1-4-alkyl)(C1-4-alkyl)NS(O)2, (C3-6-cycloalkyl)(C1-4-alkyl)NS(O)2, (C3-7-hetero-cycloalkyl)(C1-4-alkyl)NS(O)2, (hydroxy-C1-4-alkyl)2NS(O)2, (C3-6-cycloalkyl)-(hydroxy-C1-4-alkyl)NS(O)2, (C3-7-heterocycloalkyl)(hydroxy-C1-4-alkyl)-NS(O)2, H2NS(O)2N(H)C1-4-alkyl, (C1-4-alkyl)(H)NS(O)2N(H)C1-4-alkyl, (hydroxy-C1-4-alkyl)(H)NS(O)2N(H)C1-4-alkyl, (C1-4-alkyl)2NS(O)2N(H)C1-4-alkyl, (C1-4-alkyl)S(O)2N(H)C1-4-alkyl, (hydroxy-C1-4-alkyl)S(O)2N(H)C1-4-alkyl, C3-6-cycloalkyl, (C3-6-cycloalkyl)-C1-4-alkyl, (C3-6-cycloalkyl)-C1-4-alkoxy, C3-7-heterocycloalkyl, (C3-7-heterocycloalkyl)-C1-4-alkyl, (C3-7-heterocycloalkyl)-C1-4-alkoxy,                    wherein said C3-6-cycloalkyl or C3-7-heterocycloalkyl may be unsubstituted or mono- or independently polysubstituted by one or more substituents, selected from H, F, Cl, Br, CN, OH, ═O, C1-4-alkyl, hydroxy-C1-4-alkyl, halo-C1-4-alkyl, cyano-C1-4-alkyl, C1-4-alkoxy-C1-4-alkyl, hydroxy-C1-4-alkoxy, halo-C1-4-alkoxy, cyano-C1-4-alkoxy and C1-4-alkoxy-C1-4-alkoxy;                        aryl, heteroaryl, (aryl)C1-4-alkyl or (heteroaryl)C1-4-alkyl,                    wherein said aryl or heteroaryl may be unsubstituted or mono- or independently polysubstituted by one or more substituents, selected from the group consisting of H, F, Cl, Br, CN, OH, C1-4-alkyl, hydroxy-C1-4-alkyl, halo-C1-4-alkyl, cyano-C1-4-alkyl, C1-4-alkoxy-C1-4-alkyl, hydroxy-C1-4-alkoxy, halo-C1-4-alkoxy, cyano-C1-4-alkoxy and C1-4-alkoxy-C1-4-alkoxy;                        optionally in the form of a single stereoisomer or a mixture of stereoisomers, in the form of the free compound and/or a physiologically acceptable salt or a solvate thereof.        